The effect of traumatic brain injury on tau pathology by a potential seeding mechanism

The misfolding, aggregation and accumulation of specific proteins is the overarching concept in protein misfolding disorders (PMDs). The microtubule associated protein tau is known to form insoluble filaments known as neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau (pTau) found in a subset of PMDs called tauopathies, such as Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE), among others. Misfolded tau engenders a structurally alternative intermediate conformation that is prone to aggregate having amyloidogenic properties. Formation of amyloids, such as tau aggregates, is proposed to follow a nucleation-polymerization model where misfolded, soluble oligomeric seeds can trigger native proteins to misfold and aggregate. The processes responsible for the initial formation of seeding competent protein aggregates is not known. One hypothesis is that an insult to the brain could be a trigger for developing aggregate pathology noted in PMDs. Traumatic Brain Injury (TBI) is a pervasive event with an estimated 10 million people worldwide being affected and is defined as an insult to the brain caused by an external force, which may result in impaired neuronal and/or physical functioning. Indeed, TBI is a strong risk factor for PMDs, and following TBI, there is a detection of pathological tau early in human cases. TBI may be a trigger for the formation of tau seeds that can spread pathology throughout the brain. Thus, our central hypothesis is that TBI induces the early formation of tau misfolded seeds as well as exacerbates tau pathology and spreading throughout the brain by a nucleation-polymerization process, which will then lead to pathological changes relative to disease. Our overarching goal of this work is to elucidate the effect of TBI on the induction, acceleration, and spreading of tau pathology and clinical signs. To assess this, we induced tau transgenic mice with moderate-severe TBI or repetitive mild TBI (rmTBI) and examined tau pathology and spreading. Moreover, the earliest detected tau seeds induced following rmTBI were tested for seeding capability by in vivo bioassay. This proposal provides novel molecular mechanisms for these deleterious diseases, such as AD and CTE, and their link to TBI